Ray S. Lin

First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. Results: Pictilisib was well tolerated. The most common toxicities were grade 1–2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF–mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. Conclusion: Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily. Clin Cancer Res; 21(1); 77–86. ©2014 AACR.

Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non-small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without known PIK3CA hotspot mutations (0/15).Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA-mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA-mutant tumors. Cancer Discov; 7(7); 704-15. ©2017 AACR.See related commentary by Rodon and Tabernero, p. 666This article is highlighted in the In This Issue feature, p. 653.

Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.

Estimation of treatment effects in weighted log-rank tests

Non-proportional hazards have been observed in clinical trials. The log-rank test loses power and the standard Cox model generally produces biased estimates under such conditions. Weighted log-rank tests have been utilized to increase the test power; however, it is not intuitive how to interpret the test result in terms of the clinical effect. We propose a Cox-model based time-varying treatment effect estimate to complement the weighted log-rank test. The score test from the proposed model is equivalent to the weighted log-rank test, and a time-profile of the treatment effect can be obtained by fitting a time-varying covariate Cox model. Simulation results show that the proposed model preserves type-I error and achieve higher power than log-rank tests under non-proportional hazards scenarios. Whereas the standard Cox model produces biased effect estimates, the proposed model produces unbiased estimates if the weight function is correctly specified. It also achieves a better model fit and an enhanced flexibility to accommodate non-proportional hazards compared to the standard Cox model. The proposed approach makes the assumptions of the weighted log-rank test explicit and the validity of assumptions can be assessed based on prior knowledge or model goodness-of-fit. It also helps to translate the weighted log-rank test results into quantitative estimates of the treatment effect with intuitive interpretation. The proposed method can be routinely conducted to complement weighted log-rank tests, especially in the setting where non-proportional hazards are expected.

Abstract OT1-1-01: LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer

Background: Taselisib (GDC-0032) is an orally bioavailable, potent, and selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have also demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer treated with single-agent taselisib. Preclinical and clinical data also show enhanced antitumor activity when taselisib is combined with either letrozole or fulvestrant. Study design: LORELEI is a phase II, two-arm, randomized, double-blind, multicenter, neoadjuvant study of letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, stage I-III operable breast cancer. Other relevant eligibility criteria include tumor size ≥ 2 cm, unilateral disease, ECOG PS ≤1, and available and evaluable tumor tissue for central review of PIK3CA mutation analysis. Patients will be randomized (1:1) to receive continuous daily letrozole (2.5 mg) with either placebo or taselisib (4mg on a 5 days on/ 2 days off schedule) for 16 weeks. Study treatment is followed by surgery. Adjuvant treatment will be given as per physician’s discretion. Stratification at randomization is based on tumor size and nodal status. Endpoints: The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all enrolled patients and PIK3CA mutant (MT) patients. Secondary endpoints include ORR by centrally assessed MRI and pCR rate in PIK3CA wild-type (WT) patients. Other secondary endpoints performed in all enrolled patients and separately as per PIK3CA mutation status include: assessment of ORR using breast ultrasound, clinical breast exam (i.e. palpation) and mammography; changes in Ki67 levels from baseline to week 3, baseline to surgery and week 3 to surgery; centrally assessed preoperative endocrine prognostic index (PEPI) score; changes in enhancing tumor volume from baseline to surgery as measured by breast MRI via central assessment. Exploratory analyses include expression of biomarkers predictive of response to letrozole plus taselisib from tumor tissue or blood. Statistical methods: The sample size was calculated to detect an absolute percentage increase of 24% in ORR via MRI (40% in the letrozole-placebo arm vs. 64% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 16% two-sided significance level. The sample size will also detect an absolute percentage increase of 18% in pCR rate (1% in the letrozole-placebo arm vs 19% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 4% two-sided significance level. Target accrual: Approximately 330 pts at 110 global sites across Europe, North and South America, and Asia-Pacific. Reference Study ID Numbers: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38. Citation Format: Cristina Saura, Evandro de Azambuja, Peter Dubsky, Mafalda Oliveira, Kamal S Saini, Christian Fes, Ray S Lin, Timothy R Wilson, Jill Fredickson, Hema Parmar, Jerry Y Hsu, Martine Piccard, Michael Gnant, Jose Baselga. LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-01.

Abstract 415: A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC

All non-small cell lung cancer (NSCLC) patients are recommended to be screened for anaplastic lymphoma kinase (ALK)-rearrangement despite its low occurrence ( Citation Format: Hsiangmin Lu, Rachel Gonzalez, Yi Shen, Mu-lan Jin, Yipan Wu, Yungang Zhang, Kehu Yuan, Boyang Chu, Lili Qi, Huibo Liu, Chenlin Wang, Guangli Wang, Youmin Shu, Julie McDowell, Donghui Ma, Wei-wu He, Jian Chen, Ray Lin. A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 415.